Aromatic carboxylic acid amides and a process for their manufacture



ethylether and treated at Patented June ,4, 1946 UNITED STATES PATENT OFFICE AROMATIC CARBOXYLIC A PROCESS FOR THEIR Rudolf Mort, Basel, Switzerland, assignors Switzerland Arthur Stoll,

Ltd., Fribour No Drawing. Application No. 480,566. In Switze 8 Claims. (Cl.260302) The present invention relates to new therapeutically valuable aromatic carboxylic acid amides and to a process for their preparation.

It has been found that new aromatic carboxylic such as sodium carbonate, sodium acetate, dimethylaniline, pyridine, and the like.

The said carboxylic acids or their derivatives may contain in the aromatic nucleus substituents such as hydroxy groups, chlorine, substituted amino groups, nitro, cyano, nitrile, sulphonic acid alkyl, aralkyl or aryl group. As heterocyclic 5-rings we use the amino comderivatives.

The amino groups of the heterocyclic 5-ring compounds can be directly linked to the 5-ring or be bound to the same by means of any atom 7 parts of 2-aminothiazo1 are dissolved in dry compound dissolved From this solution it times from ethanol.

. high ACID AMIDES AND MANUFACTURE and Julius Peyer, to the firm Sandoz March 25, 1943, Serial rland April 17, 1942 an excess of ammonia and, alter separation, recrystallised from ethanol. The easily soluble. part of the product melts after several recrystallisations from ethanol at 142 0. (corn) and represents the 2-acetoxybenzoyl-2-amino thiazol of the formula asst l; l

000.011. on analysis the following results have been obfi IioOaNzs: Calculated, C 55.0, H 3.8, N

10.7%; found, C 55.5, H 4.1, N 10.9%.

The part of the product which ly soluble in ethanol is o-hydroxybenzoyl-Z-aminothiazol, which ha been produced by deacetylation during the reaction.

Example 2 5 parts of 2-aminothiazol are dissolved in dry benzene and treated with a solution of 9.5 parts of o-hydroxybenzoylchloride dissolved in benzene.

product is then scribed in Example 1, and recrystallised several The o-hydroxybenzoyl-2- aminothiazol sinters at 250 C. and melts while turning brown at 257 0. (corn). It possesses the formula:

if i i -o NH-C CH s OH On analysis the following values have been found: CioHsOzNzSt Calculated, C 54.5, H 3.7, N 12.7%; found, C 54.8, H 4.0, N 12.7%.

7 Example 3 3 parts of free ,B-imidazolylethylamine dried in .filtration and'standing in the cold, 2.5 parts of N (p-imidazolylethylamino) -o-hydroxybenzamide are obtained which, after several recrystalis more d'ifilcult a 3 lisations, melts at 215 C. The possesses the formula CH==(3-'CHs.CH,NH "N "NE o=c new compound and gives on analysis the following results:

C12H1302Ns: Calculated. C 62.3, H 5.6, N 18.2%;

found, C 62.7, 115.6, N 18.3%.

' Example 4 11.8 parts of 2-acetoxybenzoylchloride are dissolved in 60parts of dry chloroform. Tothis solution is added, while vigorously stirring, in small parts a solution of 5.7 parts of methylglycocyamidine in 5 parts of dry pyridine. After heating under reflux and with good stirring during 1 hour, the reaction mixture is excess of pyridine are distilled in vacuo and the residue treated with water, filtered and brought to crystallisation. After several recrystallisations from hot ,water dine) -2-hydroxybenzamide will be obtained as hydrate in pure form; it melts at 203 C. (corn) and possesses the formula On analysis the following values'have been obtained: 1

CuHuOsNa (H2O): Calculated, C 52.6, H 5.2, N 16.8%; found, C 53.0, H 5.4, N 16.8%.

Example 5 On analysis the following values have been obtained: I CrsHuOaNa: Calculated. C 66.8, H 5.2, N 13.0%;

found, c 66.9, H 5.2, N 13.1%.

Example 6 2 parts of 2-amino-4-methylthiazol are dissolved in parts of dry chloroform and treated,

4 while stirring, in 3 portions with a solution of 3.9

parts of 2-acetoxybenzoylchloride in 4 parts of 7 5 allowed to stand so for 24 hours. After this time, chloroform and the the N-(methylglycocyami- 25 azol are dissolved in the theoretical washing-out by means of dry pyridine. The reaction medium is then allowed to stand during 30 hours in the absence of water. A ,crystal paste willbe obtained from which the pyridine is extracted by a repeated water. The chloroform solution is then evaporated and the remaining reaction product crystallised from glacial acetic acid. Thus needles having a melting point of 243 0. (corn) will be obtained. The new compound possesses the formula o -c I\\\T--(\'f-Cflr NH-C on -on and on analysis gives the'following values:

C11HioOzN2S: Calculated, C 56.4, H 4.3, N 11.9%; found, C 56.5, H 4.1, N 11.9%.

Example 7 L. parts of 2-amino-4-methylthiazol are dissolved'in 50 parts of dry dioxane and treated, while vigorously stirring, at 20 C. during 15 minutes with a solution of 5.8 parts of Z-acetoxybenzoylchloride in 20 parts of dry dioxane. After standing in the cold, the di-(2-hydroxybenzoyl) amino-2:4-methylthiazol crystallises out in colorless tables. After repeated recrystallisation from dioxane the new product is purer and has the melting point of 143 C. (cam). its formula is On analysis following C1BH14O4N2S: Calculated, C 61.0, H 4.0, N 7.9%;

found, C 60.9, H 4.4, N 7.9%.

In this reaction 2 other compounds are formed which have been identified as (2'-hydroxybenzoyl)-2-amino-4-methylthiazol and its O-acetyl derivative.

Example 8 4.5 parts of 2-(2'-hydroxybenzoyl) -aminothiquantity of a half normal sodium hydroxide solution and treated at about 30 C. .under good stirring in small portions with a solution of 4.4 parts of 2-acetoxybenzoylchloride and 40 parts of a half normal sodium hydroxide solution. After standing for some time the reaction mass is neutralised with 10% hydrochloric acid and the product thus precipitated is separated. After several recrystallisations the new compound melts at 138' C. It possesses the formula on and gives on analysis the following values:

Ci'IHi204N2St Calculated, C 60.0, 113.5, N 8.2%;

found, C 60.1, H 4.0, N 8.3%.

Example 9 10 parts of 2-aminothiazol and 10 parts of pyridine are dissolved in ether, cooled downtc C. and treated in small portions with good results will be obtained? and gives on analysis, after drying in vacuo at 80 C., the following values:

CroHsONzSZ Calculated, N=13.72%; N=13.45%, 13.55%.

Example 10 colorless needles meltfound,

. cmooooOc N- on H II and crystallises in form of thin white silky needles melting at 165-l67 C.

In order to saponify the carbethoxy group the new product is dissolved in 100 parts 01' ethanol and 100 parts of a 2N sodium hydroxide solution, heated very rapidly to about 60 C., and treated with acetic acid until neutral reaction on litmus development of carbon dioxide, the 2-p-hydroxybenzoylaminothiazol precipitates in form of white thin prisms. After recrystallisation the new product melts at 252-254 C. It corresponds to the formula C t e \NH(IJ CH and gives on anaylsis the following values:

CloHsOzNzS: Calculated, N=12.73%;

Example 11 A solution of 20 parts of veratroylchloride in acetone is added, in small portions, to a solution of 22 parts of 2-aminothiazol in acetone. During the interreaction the temperature is kept by coollng at about -8 C. After standing over night found,

1 the solvent is filtered oif and the precipitate extracted by means of arate aminothiazolhydrochloride. then crystallised from ethanol and gives, on recrystallisation, long white needles or prisms meltwarm water in order to sep- The residue s.

2-benzoylaminothiazol 6 in: at 165-16'7' 'C. The 2-veratroylaminothiaml possesses the formula CHzO C onto 8 and gives on analyslsthe following values:

CizHrzOaNzS: Calculated, N ,=l0.60%; found, N=10.65%, 10.68%.

Example 12 acetic acid. For further purification it is redioxane, whereby colorless small rhombs of meltin point 207-209 C. will be obtained. The 2-anlsoyl-aminothiazol. possesses the formula and gives on analysis the following values:

CnHmOzNzS: Calculated, N=l1.97%; found, N=l1.88%,1l.99%. 1

Example 13 22 parts of Z-aminothiazoyl dissolved in a mixture of parts of pure dioxane and 100 parts of ethylether are treated at 5"10 C. with small portions of a solution of 21 parts of 2:3-hydroxynaphthoic acid chloride, dissolved in,200 parts of ether. After standing for about 2 days at room temperature, the precipitate is separated and treated with warm water in order to separate the aminothiazoi hydrochloride. The residue is then dissolved in 50% aqueous alcohol under addition of a 2 N sodium hydroxide solution. After filtration the solution is heated and treated with acetic acid until the alkaline reaction disappears. The new amide precipitates as a yellow-brownish crystalline powder, which, for further purification, is recrystallised from dioxane. Fine clear yellow needles of melting point 303-305" C. will thus be obtained.- The 2-(2z3-hydroxynaphthoyl) -aminothiazol possesses the formula and gives on analysis the following results:

C14H1002N2S: Calculated, N =10.37%; found, N=10.44%, 10.45%.

Example 14 On working in the manner described in the 0n analysis the following values have been obtained:

CrzHmONzS: Calculated, N=.1l.90%; found,

2- (2'-hydroxybenzoy1) CnHioONrSt Calculated, =12.a4-%;. found,. I N=12.91%,12.94%.

What we claim is:

1. A process forthe manufacture of a new aromatic carboxylic acid amide comprising the step of condensing Z-acetoxybenzoylchloride with 2-amlnothiazo1.

2. A process for the manufacture of a new aromatic carboxylic acid amide comprising the step of condensing two molecules of 2-acetoxybenzoylchloride with one molecule of 2-amino-4- methylthiazoL .3. A process for the manufacture of a new aromatic carboxylic acid amide comprising the step of condensing 2-acetoxybenzoylchlorlde with -aminothiazo1.

4. The amide of the formula o N--CH ism-ll lm melting at 140-142 C. 5. The amide of the formula I 0 Gig N C CH..

Ni lie l H melting 143 0.

8 6. The amide of the formula c l 0H 'meltlng at 138 C.

'7. A process for the manufacture of an acetoxyaryl carboxyllc acid amidothiazol which comprises condensing Z-acetoxybenzoylchloride with a member selected from the group consisting of 2-aminothiazo1, 2-amino-4-methy1thiazo1 and 2- (2-hydroxybenzoyl) -aminothiazol.

8. An amide of the formula wherein X is a member selected from the group consisting of Y is a member selected from the group consisting of H and CH3, the group consisting of droxyl,

and Z is a member selected from free andesterlfled hy- IARTHUR STOLL. RUDOLF MORF. JULIUS PEYER 

